Selective cell death in neurodegeneration: why are some neurons spared in vulnerable regions?

Neurodegenerative diseases exhibit varying and characteristic patterns of regional brain cell death, yet in each disorder there are distinct variations in the relative vulnerability of neurons within targeted brain regions. For example, in Parkinson's disease (PD) up to 90% of dopaminergic neurons of the ventral tier of the substantia nigra pars compacta are lost at post-mortem, while as few as 25% of dopaminergic neurons in the dorsal tier of this nucleus succumb to the disease process. To date the reasons underlying differential vulnerability of similar neurons within a defined cytoarchitectural region has received little attention. We suggest variations in protein distribution underlies this differential vulnerability. Within the substantia nigra pars compacta the more vulnerable neurons exhibit an increased expression of factors that may contribute to vulnerability (D(2) dopamine autoreceptors, GIRK-2 potassium channels, lactotransferrin and the dopamine transporter) while also expressing a relative lack of neuroprotective elements (dopamine vesicle transport protein and a number of trophic and growth factors). Differential distribution of key proteins expressed by individual cells within the same cytoarchitectural brain region may influence the severity and likelihood of common neurodegenerative mechanisms, such as protein aggregation, oxidative stress, neuroinflammation and apoptosis, and thus the eventual fate of individual cells in the disease process. An understanding of how variable protein expression can influence cell survival within the diseased human brain in a range of neurodegenerative disorders may provide avenues for the development of novel strategies to improve the survival of targeted neurons in vivo.